The proposed research will evaluate the effects of acute and daily peripheral administration of morphine and cocaine, and intra-A10 injection of enkephalin on the mesocorticolimbic dopamine and ventral striatopallidal GABA systems in rats. In vivo behavioral and neurochemical techniques will be used, and in vitro receptor density and mRNA levels will be measured. All three compounds produce an acute motor stimulant response, and following daily administration the motor stimulant response is augmented. It is hypothesized that daily administration of morphine, cocaine and enkephalin produces behavioral sensitization by modifying the response of A10 dopamine neurons to afferent input, and that this will be reflected in alterations in dopamine release in the nucleus accumbens and A10 region, and in GABA release in the ventral pallidum and A10 region. Release will be estimated by measuring extracellular dopamine and GABA levels with intracranial dialysis. It is also proposed that behavioral sensitization may be reflected in changes in dopamine D1, dopamine D2, mu opioid, delta opioid or GABAA receptors in discrete brain nuclei as measured by receptor autoradiography. Also, in situ hybridization will be used to determine the effects of acute and daily drug treatment on mRNA for tyrosine hydroxylase, glutamic acid decarboxylase, Gi2 subunit or D2 receptors. Finally, the effect of manipulating: 1) D1, D2 or GABAB receptors, 2) potassium channels, or 3) the Gi/Go subunits of GTP binding protein, in the A10 region on the acute and daily effect of cocaine, morphine or enkephalin will be determined. Behavioral sensitization produced by the long-term use of cocaine is manifested clinically as an augmentation of paranoid behaviors. By determining the underlying anatomical substrates and cellular mechanisms mediated sensitization to cocaine and opioids in rats, it is possible that more rational therapy can be designed for intervention in human drug abuse where sensitization is thought to be a factor.